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Objective: Poor tumor differentiation status is associated with worse patient outcome in colorectal cancer. However, the molecular basis for loss of differentiation in colon cancer is not well understood. We have found that the transcription factor Ets homologous factor (EHF) is highly expressed in the normal human and mouse colonic epithelium and is down-regulated in poorly-differentiated colorectal cancer cell lines. The aim of this study was to investigate the role of EHF in regulating normal colonic epithelial cell differentiation in vivo. Methods: A novel mouse model was generated in which the Ets DNA binding domain (exon 8) of EHF was flanked by loxP sites (EHFlox/lox). To inactive EHF in the intestinal epithelium, EHFlox/lox mice were crossed to Villin-CreERT2 mice and recombination induced by tamoxifen treatment. Tamoxifen and vehicle treated mice were monitored weekly for up to one year. At each endpoint, tissue was collected and the effect of EHF deletion on intestinal cell proliferation and differentiation assessed by qRT-PCR and immunohistochemistry. Results: Targeted inactivation of EHF in the small intestinal and colonic epithelium following tamoxifen treatment was confirmed at the DNA and RNA level. EHF inactivation in the intestinal epithelium had minimal effect on survival, weight gain and overall health of the animals. Furthermore, loss of EHF did not markedly affect cell proliferation or the overall architecture of the intestinal epithelium. Finally, EHF inactivation also had minimal effect on markers of absorptive, enteroendocrine or Paneth cell differentiation but did reduce the number of goblet cells in the colonic epithelium. Conclusion: EHF does not play a major role in regulating cell proliferation in the mouse intestine but may play a role in regulating goblet cell differentiation. The role of EHF in intestinal tumourigenesis and response to stress are currently being investigated. Citation Format: Camilla M. Reehorst, Ian Y. Luk, Rebecca Nightingale, Mercedes Davalos-Salas, Amardeep S. Dhillon, John M. Mariadason. Investigating the in vivo role of the EHF transcription factor in intestinal epithelial differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2017-3529